scholarly journals Clonal Hematopoiesis Is Associated with Increased Risk of Progression of Asymptomatic Waldenström Macroglobulinemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2678-2678
Author(s):  
Sabrin Tahri ◽  
Tarek H Mouhieddine ◽  
Robert A. Redd ◽  
Luisa Maria Lampe ◽  
Katarina Nillson ◽  
...  
Keyword(s):  
Research Funding ◽  
Adverse Outcomes ◽  
Waldenström Macroglobulinemia ◽  
Clonal Hematopoiesis ◽  
Non Hodgkin Lymphoma ◽  
Dana Farber Cancer Institute ◽  
Waldenstrom Macroglobulinemia ◽  
Increased Risk ◽  
Significant Difference ◽  
Risk Of Progression

Abstract Introduction Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström Macroglobulinemia (WM) and its association with clinical outcomes. Methods We retrospectively reviewed clinical data of 602 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM), and WM who had clinical next-generation sequencing (NGS) performed on bone marrow aspirates or peripheral blood obtained between October 2014 and February 2020 at the Dana-Farber Cancer Institute. An Illumina Truseq amplicon-based NGS assay of 95 genes recurrently mutated in myeloid and lymphoid neoplasms was utilized. Each specimen yielded ~2 million reads and ~1500X average coverage, with 90% of amplicons having >200X coverage. Pathogenic driver variants were identified based on mutation type, position, and frequency in published reports and public databases. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA). Results The cohort included 147 patients with MGUS or asymptomatic WM and 453 patients with symptomatic WM, with a median age of 66 years (range = 40-89) and 68 years (range = 33-93), respectively, at the time of first NGS assay. The prevalence of CH-DTA was 14% in symptomatic WM patients and did not differ significantly in MGUS (13%) or SWM (14%). Among precursor patients, there was an increased risk of progression to symptomatic WM for those with CH-DTA [7/20 patients with vs. 11/116 without CH-DTA progressed over a median of 54 months (P = 0.002)]. In symptomatic WM patients, CH-DTA was positively associated with older age (P < 0.001) at the time of NGS, with a median age of 72 vs. 67 years for patients with versus those without CH-DTA. CH-DTA was not associated with inferior overall survival (OS) with a relatively short median follow-up from diagnosis and NGS assay. OS was 6.7 years (95% CI = 6.1-7.6) for patients with CH-DTA and 2.5 years for patients without DH-DTA (95% CI = 2.2-2.8). The most common cause of death was disease progression, with no significant difference between those with or without CH-DTA. Patients with CH-DTA had an increased risk of cardiovascular disease (30% vs. 18%, P = 0.036). Conclusions We demonstrate that CH is common in WM patients and is associated with an increased risk of progression from precursor states but not with inferior survival. Further work is needed to determine how the presence of CH might promote progression to WM and whether it can be incorporated into future risk stratification models. Importantly, our data do not support changes in clinical management or alterations in therapy for patients with WM and coexistent CH and reinforce the need to interpret NGS results within their specific clinical context. Disclosures Steensma: Novartis: Current Employment. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Treon: X4: Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Sperling: Adaptive: Consultancy.

scholarly journals Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia

2021 ◽  
Author(s):  
Sabrin Tahri ◽  
Tarek H Mouhieddine ◽  
Robert A Redd ◽  
Luisa M Lampe ◽  
Katarina I Nilsson ◽  
...  
Keyword(s):  
Monoclonal Gammopathy ◽  
Somatic Mutations ◽  
Adverse Outcomes ◽  
Clinical Effects ◽  
Waldenström Macroglobulinemia ◽  
Clonal Hematopoiesis ◽  
Non Hodgkin Lymphoma ◽  
Waldenstrom Macroglobulinemia ◽  
Increased Risk ◽  
Risk Of Progression

Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström macroglobulinemia (WM) and its association with clinical outcomes. In order to unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2 or ASXL1 (DTA) and was detected in 14% of 587 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM) or WM. The presence and size of DTA clones was associated with older age. Patients with CH had an increased risk of progression from MGUS or SWM to WM but not worse overall survival in this cohort. These findings further illuminate the clinical effects of CH in patients with indolent NHL such as WM.

scholarly journals Clonal Hematopoiesis Associated with Adverse Outcomes Following Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 986-986 ◽  
Author(s):  
Christopher J. Gibson ◽  
R. Coleman Lindsley ◽  
Vatche Tchekmedyian ◽  
Jiantao Shi ◽  
Brenton G. Mar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Adverse Outcomes ◽  
Sequencing Data ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
Exome Sequencing Data ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon characterized by the presence of somatic mutations in peripheral blood (PMIDs: 25426837, 25426838). Although CHIP was originally defined in healthy older adults without cytopenias, it can be found in other contexts as well. For example, one recent report described four patients with therapy-related myeloid neoplasm (TMN) arising after treatment for other cancers, all of which were driven by TP53 mutations that could be found at very low levels in samples drawn years before the development of TMN (PMID: 25487151). However, there has not yet been a more systematic study of CHIP in this type of context. In this study, we sought to understand how CHIP behaves and influences outcomes in the context of autologous stem cell transplantation (ASCT), arguably the most extreme selective pressure that can be studied in the context of native hematopoiesis. We hypothesized that in patients with Non-Hodgkin Lymphoma (NHL) undergoing ASCT, the presence of CHIP at the time of transplantation would be associated with an increased risk of TMN and other adverse outcomes. Methods We analyzed exome sequencing data from 10 patients with TMN after ASCT (City of Hope Cancer Center, Duarte, CA), and performed targeted sequencing of 116 genes on banked, mobilized peripheral blood from an additional 401 patients with NHL who underwent ASCT (Dana Farber Cancer Institute, Boston, MA), to determine whether there is a clonal connection between CHIP at the time of ASCT and subsequent TMN, and to determine whether the presence of CHIP at the time of ASCT influences subsequent outcomes. Results In 7 of 10 TMN patients for whom we analyzed exome sequencing data, mutations present at the time of TMN were also detectable in the pre-ASCT sample. PPM1D, a key mediator of the DNA damage pathway, was mutated in 2 patients, as was TP53 (2 patients), TET2 (2 patients) and PRPF8 (1 patient). In our larger cohort of 401 unselected ASCT patients, CHIP was common (121 patients, 30.2%) and was associated with older age but not with other demographic or treatment-related factors. PPM1D was the most commonly mutated gene (54 mutations in 48 patients). In the ASCT cohort of 401 patients, 18 patients developed TMN. The presence of CHIP at the time of ASCT significantly increased this risk: the 10-year cumulative incidence of TMN, with death and allogeneic transplant as competing risks, was 12.4% for patients with CHIP, compared to 3.5% for patients without CHIP (P=0.002, Figure 1A). Moreover, the presence of CHIP at the time of ASCT conferred significant risks beyond TMN alone, as patients with CHIP had significantly inferior overall survival compared to patients without CHIP (10-year OS 30.6% versus 60.9%, P=0.0003, Figure 1B). This difference was driven primarily by late mortality and not by an increased risk of relapse or by the difference in rate of TMN. Although other variables were associated with OS in univariate analysis, multivariate analysis in a Cox proportional hazards model showed that only older age (60 or above), aggressive lymphoma, and presence of CHIP were significantly associated with survival. Conclusion We show that CHIP at the time of ASCT for NHL is common and is associated with an increased risk of TMN and decreased overall survival independent of the TMN risk. These results have substantial clinical and translational implications. They suggest the need to specifically study the connection between CHIP and lymphoma more deeply, which could be accomplished by assessing CHIP in patients with newly diagnosed lymphoma prior to the administration of any chemotherapy or mobilizing agents. They also suggest the need to consider alternative therapeutic approaches for patients with lymphoma and a high risk of TMN who are being considered for ASCT. Finally, they underscore the need to study clonal hematopoiesis in the context of treatment for other cancers to determine whether these results may be relevant to an even larger number of patients. Disclosures Lindsley: MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy. Mar:H3 Biomedicine: Other: Spouse's employment. LaCasce:Forty Seven: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy. Koreth:LLS: Research Funding; amgen inc: Consultancy; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; kadmon corp: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 150-150
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Chia-jen Liu ◽  
Efstathios Kastritis ◽  
Geoffrey Fell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Proportional Hazards ◽  
Risk Group ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Risk Of Progression

Abstract Background. Waldenström macroglobulinemia (WM) is a low-grade non-Hodgkin's lymphoplasmacytic lymphoma associated with overproduction of monoclonal IgM protein. It is preceded by an asymptomatic stage, called Smoldering Waldenström Macroglobulinemia (SWM), associated with a high risk of progression to overt disease. Current understanding of progression risk in SWM is based on a few small studies, and it is still unclear how to distinguish the asymptomatic patients who will progress from those who will not. Patients and Methods. We obtained clinical data of all WM patients who had been diagnosed and followed up at Dana-Farber Cancer Institute from 1982 to the end of 2014. Only patients with asymptomatic disease at the time of diagnosis were included in this study to identify risk factors for disease progression. Patients who received chemotherapy for a second cancer, before or after asymptomatic WM diagnosis (n =24), were excluded as chemotherapy might have affected the natural course of disease. Patients who progressed to or were diagnosed later with other types of B-cell lymphoproliferative disorders or Amyloidosis (n =71) and patients with myeloproliferative disorders or thalassemia (n = 4) were all excluded from our cohort. Furthermore, we excluded patients with no morphologic evidence of lymphoplasmacytic infiltration in the bone marrow biopsy (n =37), those without a bone marrow biopsy done at time of diagnosis (n =21), and those who were treated for peripheral neuropathy alone (n =13). Progression was defined based on the Consensus Panel recommendations of the Second International Workshop on WM. Survival analysis was performed using the Kaplan-Meier method and differences between the curves were tested by log-rank test. Effects of potential risk factors on progression rates was examined using Cox proportional-hazards models, with hazard ratios (HRs) and associated 95% confidence intervals (CIs). Results. A total of 439 patients were included in the study. During the 35-year study period and a median follow up of 7.8 years, 317 patients (72.2%) progressed to symptomatic WM. The median time to progression was 3.9 (95% CI 3.2-4.6) years. In the multivariate analysis, IgM ≥ 4,500 mg/dL (adjusted HR 4.65; 95% CI 2.52-8.58; p < 0.001), BM lymphoplasmacytic infiltration ≥ 70% (adjusted HR 2.56; 95% CI 1.69-3.87; p < 0.001), β2-microglobulin ≥ 4.0 mg/dL (adjusted HR 2.31; 95% CI 1.19-4.49; p = 0.014), and albumin < 3.5 g/dL (adjusted HR 2.78; 95% CI 1.52-5.09; p = 0.001) were all identified as independent predictors of disease progression, suggesting those thresholds could be clinically useful for determining high-risk patients. On the other hand, given the continuous nature of these variables, we built a proportional hazards model based on four variables (Bone marrow infiltration percentage, serum IgM, albumin, β2-microglobulin). The model divided the cohort into 3 distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.9 years (95% CI 1.64-2.13), an intermediate-risk group with median TTP of 4.6 years (95% CI 4.31-5.15), and a low-risk group with a median TTP of 8.1 years (95% CI 7.33-8.13)(See Figure). To enhance its clinical applicability, we made the model available as user interface through a webpage and mobile application, where clinicians can enter an individual SWM patient's lab values and get information regarding their risk group and estimated individual risk of progression to symptomatic WM. Conclusion. We have assembled the largest cohort of SWM patients to date, which allowed us to identify four independent predictors of progression to overt disease: BM infiltration ≥ 70%, IgM ≥ 4,500 mg/dL, b2m ≥ 4.0 mg/dL and albumin < 3.5 g/dL. Using those variables in a proportional hazards model, we developed a robust, flexible classification system based on risk of progression to symptomatic WM. This system stratifies SWM patients into low-, intermediate- and high-risk groups and thus has the potential to inform patient monitoring and care. Most importantly, it can help identify high-risk patients who might benefit from early intervention in this rare malignancy. Figure 1. Figure 1. Disclosures Bustoros: Dava Oncology: Honoraria. Kastritis:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Genentech: Consultancy; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Ghobrial:BMS: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

scholarly journals The High Risk for Symptomatic Hyperviscosity in Patients with High Serum IgM Levels Can be Used to Support Initiation of Treatment in Waldenström Macroglobulinemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2983-2983
Author(s):  
Joshua Gustine ◽  
Kirsten Meid ◽  
Robert R Manning ◽  
Toni Dubeau ◽  
Irene M. Ghobrial ◽  
...  
Keyword(s):  
Research Funding ◽  
Treatment Initiation ◽  
Hazard Analysis ◽  
Signs And Symptoms ◽  
High Serum ◽  
Clinical Feature ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Risk Increase ◽  
Increased Risk

Abstract Introduction: Hyperviscosity syndrome (HVS) is a clinical feature associated with Waldenström macroglobulinemia (WM). The overproduction of an IgM paraprotein can increase serum viscosity and induce signs and symptoms of HVS, prompting the need for WM-directed therapy. Current consensus panel guidelines recommend initiating treatment only for symptomatic HVS rather than a specified serum IgM level (Kyle et al, 2003). However, many clinicians treat for an elevated IgM in the absence of hyperviscosity-related findings to pre-empt HVS and any associated sequelae. Empiric treatment for WM patients with high serum IgM levels has been proposed as a reasonable criterion for treatment initiation regardless of symptomatic status due to the risk of HVS (Treon, 2015). We therefore sought to determine the serum IgM level threshold for which the risk of HVS would be supportive of treatment initiation. Methods: We identified 825 untreated patients who met the consensus diagnosis for WM (Owen et al, 2003), and who received care in the WM clinic at our Institution between January 1999 and June 2016. The occurrence of symptomatic HVS was then determined, and serum IgM levels at the time of HVS diagnosis were stratified. For patients with an IgM >=3,000 mg/dL, a stratified hazard analysis was performed to compare the risk of HVS associated with increasing serum IgM levels. The outcome of interest was hazard ratio (HR) with 95% confidence interval (CI). P-values <0.05 were considered statistically significant. Results: Among 825 untreated patients, 112 (14%) cases of HVS were identified. The incidence of HVS in patients with serum IgM levels between 3000-3999, 4000-4999, 5000-5999, 6000-6999 and >=7000 mg/dl was 3%, 22%, 30%, 61% and 79%, respectively. The HR of HVS in patients with serum IgM levels 4000-4999, 5000-5999, 6000-6999 and >=7000 mg/dl was 7.5 (95% CI 3.4-16.8), 9.8 (95% CI 4.7-20.4), 28.2 (95% CI 13.2-60.3) and 26.8 (95% CI 12.5-57.7), respectively (IgM 3000-3999 was baseline; Figure 1A). When compared to patients with a serum IgM 3,000-5,999 mg/dL, patients with a serum IgM >=6,000 mg/dL had a 4.9-fold increased risk for development of HVS (HR 4.87, 95% CI 3.06-7.56; Figure 1B). No symptomatic HVS was observed among patients with a serum IgM <3,000 mg/dL. HVS patients with a serum IgM level >=6,000 mg/dL were significantly more anemic and thrombocytopenic, as well as more likely to have a serum B2M >3.0 mg/dL. HVS patients with a serum IgM >=6,000 mg/dL were also more likely to receive emergent plasmapheresis versus those HVS patients with a serum IgM 3,000-5,999 mg/dL (77% vs. 58%; p=0.04). All but one patient received WM-directed intervention in response to symptomatic HVS; one patient refused treatment. Conclusion: Patients with a serum IgM >=6,000 mg/dL are at a significantly increased risk for developing symptomatic HVS. Given the magnitude of the risk increase described herein for symptomatic HVS, a serum IgM >=6,000 mg/dL may reasonably be considered as a criterion for initiation of WM-directed therapy. Figure Figure. Disclosures Ghobrial: Amgen: Honoraria; Noxxon: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria. Castillo:Otsuka: Consultancy; Abbvie: Research Funding; Biogen: Consultancy; Janssen: Honoraria; Millennium: Research Funding; Pharmacyclics: Honoraria.

scholarly journals Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma

2017 ◽  
Vol 35 (14) ◽  
pp. 1598-1605 ◽  
Author(s):  
Christopher J. Gibson ◽  
R. Coleman Lindsley ◽  
Vatche Tchekmedyian ◽  
Brenton G. Mar ◽  
Jiantao Shi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Exome Sequencing ◽  
Hodgkin Lymphoma ◽  
Autologous Stem Cell Transplantation ◽  
Adverse Outcomes ◽  
Clonal Hematopoiesis ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

scholarly journals Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies

2020 ◽  
Vol 38 (11) ◽  
pp. 1198-1208 ◽  
Author(s):  
Steven P. Treon ◽  
Lian Xu ◽  
Maria Luisa Guerrera ◽  
Cristina Jimenez ◽  
Zachary R. Hunter ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
B Cell Lymphoma ◽  
Mutation Status ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Genomic Landscape ◽  
Rational Drug ◽  
Increased Risk ◽  
Impact On Treatment ◽  
Btk Inhibitor

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.

Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenström macroglobulinemia

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2918-2923 ◽  
Author(s):  
Sandra Grass ◽  
Klaus-Dieter Preuss ◽  
Alexandra Wikowicz ◽  
Evangelos Terpos ◽  
Marita Ziepert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Immunoglobulin A ◽  
Cell Receptor ◽  
Carrier State ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Phosphatase Treatment ◽  
Increased Risk ◽  
Undetermined Significance

Abstract We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenström macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay. The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti–P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio = 6.2; P = .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgM-MGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk.

Phase II Trial of the mTOR Inhibitor RAD001 in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: The Dana Farber Cancer Institute Experience.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1011-1011
Author(s):  
Irene M. Ghobrial ◽  
Stacey Chuma ◽  
Amy Sam ◽  
Renee Leduc ◽  
Marybeth Nelson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Significant Activity ◽  
Waldenström Macroglobulinemia ◽  
Overall Response ◽  
Dana Farber Cancer Institute ◽  
Waldenstrom Macroglobulinemia ◽  
Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of the mTOR inhibitor RAD001 in low- grade lymphomas. Our preclinical studies demonstrated activity of mTOR inhibitors in Waldenstrom Macroglobulinemia (WM) cell lines and patient samples. This phase II study aimed to determine safety and activity of the oral mTOR inhibitor RAD001 (Novartis Pharmaceutical, MA) in patients with relapsed or refractory WM. METHODS: Patients who had at least one previous therapy for WM, and who had symptomatic relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received daily RAD001 at 10 mg. A cycle was considered 28 days. Patients were allowed to stay on therapy until progression of disease or excessive toxicity. This study was conducted in a collaborative effort between Dana Farber Cancer Institute (DFCI) and Mayo Clinic College of Medicine. Here, we report the data on the patients accrued at DFCI. RESULTS: 19 pts (15 men and 4 women) have been treated to date. All patients had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including included rituximab, nucleoside analogues (fludarabine or 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3330 mg/dL (range 1010– 7410). The median follow on RAD001 was 8 months (range 3 – 22 months). Eighteen pts are currently evaluable for response. Best responses to RAD001 after 2 cycles using IgM monoclonal protein were as follows: partial remission in 8 (44%), minimal response in 5 (28%). Progressive disease occurred in 4 (22%) and stable disease occurred in 1 (6%). The overall response rate (PR+MR) was 72%. The median duration of response has not been reached (3–22+ months). Patients tolerated therapy well without significant toxicities. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 1 patient, grade 3 pneumonia in 1 patient, grade 3 hyperglycemia in 1 patient and grade 3 mucositis in 1 patient. Other adverse events of grade 2 or lower included nail cracking, mucositis, diarrhea, and fatigue. Attributable toxicities otherwise proved manageable with appropriate supportive care, and RAD001 was generally well tolerated. One patient enrolled on the study withdrew consent and changed to hospice care within 3 weeks of therapy, and passed away due to disease progression. CONCLUSIONS: The use of the oral RAD001 single agent RAD001 in patients with relapsed or refractory WM was welltolerated and demonstrated significant activity achieving an overall response rate in 72% of patients. Future studies of combination of this agent with rituximab and bortezomib are currently being planned.

Changing Epidemiology and Improved Survival In Patients With Waldenstrom Macroglobulinemia: Review Of Surveillance, Epidemiology, and End Results (SEER) Data

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3135-3135 ◽  
Author(s):  
Sydney Nelson ◽  
Lawrence H. Boise ◽  
Jonathan L. Kaufman ◽  
Leonard T Heffner ◽  
Nishi N Shah ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Median Survival ◽  
Survival Benefit ◽  
Research Funding ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Seer Data ◽  
Waldenström's Macroglobulinemia ◽  
End Results ◽  
New Millennium

Abstract Background Waldenstrom Macroglobulinemia (WM) is a hematological malignancy that affects 1500 people each year in the United States. Due to lack of literature on era comparative population-based analysis, we have analyzed Surveillance Epidemiology and End Results (SEER) data to evaluate the changes in incidence and survival patterns in the new millennium where modern therapeutic agents such as rituximab, immunomodulatory drugs and proteasome inhibitors were offered to WM patients; in contrast to the earlier period when they were non-existent. Methods The SEER 18 registry which includes data from 1973-2010 from 18 geographic areas including 28% of US representative population was used in analysis. ICD-O-3 code 9761 was used for identifying patients for this analysis. SEER* Stat 8.0.4 is used to calculate age-adjusted incidence and mortality rates based on race, gender, and age for patients. Age adjusted rates were used in this anlaysis to avoid confounding variables when comparing rates over time. Results We have included 4304 patients in the analysis (1244 patients diagnosed before 2000 and 3060 patients after 2000). The incidence rate of WM increased with age. The 10 year cumulative incidence rate per 100,000 by age stratification (<50 yrs, 50-59 yrs, 60-69 yrs, 70-79 yrs and >80) are 0.02%, 0.40%, 1.01%, 2.14% and 2.98% respectively. Over the last decade the trend of incidence rate in WM has been steadily decreasing across all age groups (Figure 1). Median survival for all WM patients is 74 months (m) (70.2-77.8). Significant survival improvement was seen in the current era (median survival ≥2000 vs. <2000: 84 m (79.8-92.2) vs. 64 m (57-67); p=0.000) Survival difference ≥2000 vs. <2000 was seen across most groups (male: 83 m vs. 58 m, p=0.000; female: 87 m vs. 70 m, p=0.004; white: 85 m vs. 62 m, p=0.000; age 50-59: 122 vs NR; p=0.002; age 60-69: 123 vs. 81 m; p=0.000; age 70-79: 69 vs. 53 m; p=0.001; age >80: 36 vs. 31 m; p=0.05). Younger patients <50 (NR vs. 204 m, p=0.53) and African American patients (75 m vs. 62 m, p=0.72) did not see survival benefit. Conclusion The incidence rates of Waldenstrom's macroglobulinemia are trending down over the last decade for reasons unclear. The survival rates have significantly improved across most stratifications of age, sex, gender in the new millennium. These results could be secondary to the favorable impact of new drugs used in treating patients with Waldenstrom's macroglobulinemia. Also should be taken into consideration, that the current classification for WM took place in the new millennium which is a limitation for interpretation of this survival benefit observed. Disclosures: Boise: Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Heffner:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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